A great number of potent drugs and potential drug candidates have a low solubility in water or aqueous solutions, thus limiting their scope of use. Formulation of poorly soluble drugs, such as paclitaxel (PTX) with a water solubility of approx. 1 μg/mL, remains a major challenge in drug delivery (Huh, K. M., et al., J. Controlled Release 126, 122-129 (2008); Dabholkar, R. D., et al. Int. J. Pharm. 315, 148-157 (2006); Yang, T., et al., Int. J. Pharm. 338, 317-326 (2007); Torchilin, V. P., Cell. Mol. Life. Sci 61, 2549-2559 (2004); Haag, R., Angew. Chem. Int. Ed. 43, 278-282 (2004)). The current clinical formulation of PTX, Taxol®, contains less than 1% w/w of active drug, but 99% w/w of excipients know to cause considerable side effects for the patients. Similar problems are encountered with active agents in other technical areas, such as plant protection, etc. Various methods to solubilize or disperse active agents have been developed. Traditional methods are typically based on the use of solvents, surfactants or chelating agents. These methods have one or more disadvantages related to toxicity of the excipients, limited stability of the formulations in aqueous media, in particular upon dilution, or difficult formulation procedures.
It is therefore necessary or beneficial to be able to solubilize or formulate hydrophobic drugs in aqueous media. The solubilized drugs may have improved dispersion in the aqueous media and/or increased stability in the aqueous dispersions.
Various methods to solubilize or disperse drugs have been developed. These methods are typically based on the use of solvents, surfactants, chelating agents or other drug delivery systems such as liposomes. These methods have one or more disadvantages related to the toxicity of the excipients, difficult formulation procedures, and/or limited stability of the formulations in aqueous media. Stability is a particularly problematic upon the dilution encountered when administered to a patient.
Copolymers comprising at least one hydrophilic and one hydrophobic block (amphiphilic block copolymers) have been shown to be effective for the solubilization of drugs of limited solubility in aqueous media.
More recently, liposomes (Wu, J., et al., Int. J. Pharm. 316, 148-153 (2006)), micro- and nanoparticles (Desai, N. P. et al., Anti-Cancer Drugs 19, 899-909 (2008)) and polymer micelles (Huh, K. M., et al., J. Controlled Release 126, 122-129 (2008); Konno, T., et al., J. Biomed. Mat. Res., Part A, 65A, 210-215 (2002); Kim, S. C., et al., J. Controlled Release 72, 191-202 (2001)) have been studied intensively as solubilisation/drug delivery systems, each approach having advantages and disadvantages. One major limitation of polymer micelles is the loading capacity and the total amount of drug that can be solubilized.
U.S. Patent Application Publication No. 2004/0185101 discloses polymeric compositions with the capability to solubilize hydrophobic drugs in aqueous media. The biodegradable ABA-type or BAB-type block copolymers used in this approach can markedly increase the solubility of hydrophobic drugs, such as paclitaxel, in aqueous solution. However, one disadvantage of this approach is that the amount of polymer excipient is very high, typically between 10 and 30%. Moreover, the loading capacity of these compositions is very limited with a loading capacity of <10% (w/w) for paclitaxel and less than 1% (w/w) for cyclosporin A.
Poly(2-oxazoline)s have recently attracted considerable attention for biomedical applications. Of particular interest are hydrophilic poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-ethyl-2-oxazoline) (PEtOx) as they exhibit stealth (Zalipsky, S., et al., J. Pharm. Sci. 85, 133-137 (1996); Woodle, M. C., et al., Bioconjugate Chem. 5, 494-496 (1994)) and protein repellent effects (Konradi, R., et al., Langmuir 24, 613-616 (2008)) and undergo rapid renal clearance (Gaertner, F. C., et al., J. Controlled Release 119, 219-300 (2007)) similar to poly(ethylene glycol), a commonly used polymer for injectable drug delivery systems.
To date, few nontoxic biocompatible formulations are known for the solubilization of paclitaxel. The only formulation commercially available utilizes a 1/1 mixture of Cremophor EL® and dehydrated ethanol (v/v). While this formulation is able to solubilize relatively large amounts of paclitaxel (6 mg/ml) in the pure formulation which must then be diluted to obtain in administrable aqueous solution), it can also cause severe side effects in patients. It is therefore highly desirable to find new ways to formulate paclitaxel and other drugs in aqueous media suitable for intravenous injection to patients.
It is the aim of the present invention to provide compositions containing a delivery system which allows active agents, in particular hydrophobic active agents, to be efficiently solubilised and/or formulated. In particular, the compositions should be simple to prepare and provide a high loading capacity for the subject active agent.